Funding for this supplement has been provided by Wyeth Pharmaceuticals

 

Dr. Shelton is James G. Blakemore Research Professor of Psychiatry and Professor of Pharmacology, and Vice Chair for Research in the Department of Psychiatry at Vanderbilt University School of Medicine in Nashville.

Disclosure: Dr. Shelton is a consultant to Eli Lilly, Evotec, Forest, Gedeon-Richter, Janssen, Merck, Otsuka, Pamlab, and Sierra; and receives grant support from Bristol-Myers Squibb, Eli Lilly, Forest, Janssen, the National Institutes of Health, Novartis, Otsuka, Pamlab, and Pfizer. Dr. Shelton discusses unapproved/investigational uses of milnacipran for the treatment of major depressive disorder.

Acknowledgment: The author would like to thank Kathleen Dorries, PhD, and Lorraine Sweeney, BA, of Advogent for assisting in the writing and editing of this article.

Please direct all correspondence to: Richard C. Shelton, MD, Department of Psychiatry, Vanderbilt University School of Medicine, 1500 21st Avenue, South, Suite 2200, Nashville, TN 37212; Tel: (615) 343-9669; Fax: (615) 343-9038; E-mail: richard.shelton@vanderbilt.edu.


 

Focus Points

• The serotonin norepinephrine reuptake inhibitors (SNRIs) venlafaxine, duloxetine, milnacipran, and desvenlafaxine all bind the serotonin and norepinephrine transporters, but the potency with which they bind each of these—and their selectivity ratios—differ.
• SNRIs vary in their potential to influence cytochrome P450 (CYP)-mediated drug-drug interactions, but, in general, they interact less with CYP 450 compounds, particularly the important isozyme CYP 2D6, than do selective serotonin reuptake inhibitors (SSRIs).
• SNRIs demonstrate efficacy that is comparable to or better than that of tricyclic antidepressants and SSRIs in meta- and pooled analyses, but there are few studies addressing differences in efficacy within the class.
• The safety and tolerability profiles of SNRIs are similar to those of SSRIs; however, SNRIs may be associated with dose-related increases in blood pressure and lower rates of sexual dysfunction compared with certain SSRIs.
 

Abstract

Serotonin norepinephrine reuptake inhibitors (SNRIs) are increasingly being used as first-line treatment for major depressive disorder (MDD). This article discusses differences in the pharmacology and pharmacokinetics of the members of this class of antidepressants and compares their efficacy and tolerability to those of other agents used to treat MDD. The SNRIs have relatively short half-lives and display linear pharmacokinetics. In general, these drugs interact less with cytochrome P450 (CYP) compounds, especially the important isozyme CYP 2D6, than do selective serotonin reuptake inhibitors (SSRIs), suggesting a reduced potential for drug-drug interactions. Overall, SNRIs demonstrate efficacy that is comparable to or better than that of tricyclic antidepressants and SSRIs. They are also effective in treating a broad range of psychiatric illnesses associated with MDD, but additional studies are needed to determine optimal treatment for these comorbid conditions. Although SNRIs as a class exhibit many similarities, individual agents differ in their pharmacokinetic and safety profiles. Furthermore, the range of selectivity ratios observed with these agents implies that differences in serotonergic and noradrenergic levels may exist, which could have important clinical implications. These factors, along with genetic variations in individual patients and the pharmacologic profiles of concomitant medications, must be considered when selecting an SNRI for treatment of MDD.

Introduction

The four medications that comprise the serotonin norepinephrine reuptake inhibitor (SNRI) class—venlafaxine, duloxetine, milnacipran, and desvenlafaxine (administered as desvenlafaxine succinate)—share similarities in structure and mechanism, but differences in their pharmacology and pharmacokinetics can affect their efficacy and tolerability profiles. Each of the SNRIs has been approved in the United States or in other countries for the treatment of major depressive disorder (MDD), and all but the newest SNRI, desvenlafaxine, have been approved for additional indications.1-5 This article assesses the similarities and differences among members of the SNRI class in pharmacology and pharmacokinetics, efficacy in the treatment of MDD, and safety and tolerability. As the first available SNRI, venlafaxine has been well studied in each of these areas. There are far fewer studies assessing milnacipran, which has not been approved by the Food and Drug Administration for treatment of MDD (although it is approved by drug regulatory agencies outside the US), and desvenlafaxine, which was approved in the US in 2008.4 Few head-to-head studies have been published to date comparing the efficacy of the different SNRIs for any indication; thus much of the available data comes from comparisons between SNRIs and antidepressants of other classes.

Pharmacology and Pharmacokinetics

Pharmacology

The SNRIs venlafaxine, duloxetine, milnacipran, and desvenlafaxine all bind the serotonin (5-HT) and norepinephrine (NE) transporters, but the potency with which they bind each of these and the selectivity ratios differ (Table 1).1-4,6-9 The estimated 5-HT:NE selectivity ratios for the SNRIs are shown in comparison to antidepressant drugs of other classes in Table 2.7-11

 

 

In radioligand binding studies in rat brain membranes, venlafaxine was shown to have a relatively low affinity for both the 5-HT and NE transporters.12 However, binding is much higher for the human 5-HT transporter than for the human NE transporter; the 5-HT:NE ratio was estimated at 1:30 in one study.7 In vivo studies in healthy human subjects demonstrated that venlafaxine inhibits platelet 5-HT uptake across its dose range, whereas it inhibits NE uptake (as measured by the pressor response to intravenous tyramine) only at higher doses (ie, ≥225 mg/day).13 Positron emission tomography (PET) studies in healthy human subjects administered venlafaxine show that 5-HT transporter occupancy in the striatum increases modestly but significantly from the minimal clinical dose of 75 mg/day (~80% occupancy) to 225–450 mg/day (~85% occupancy).14,15 Four selective serotonin reuptake inhibitors (SSRIs) were also assessed, and all showed ~80% occupancy at their respective minimum recommended clinical dosage.14

Duloxetine has a higher affinity for both the 5-HT and NE transporters than venlafaxine. In vitro, duloxetine potently inhibits 5-HT and NE uptake in rat hypothalamus and cerebral cortex.16 In ex vivo studies, administration of duloxetine 1 hour prior to sacrifice causes dose-dependent and parallel decreases of 5-HT and NE uptake in rat hypothalamus, which is consistent with significant NE uptake blockade at relatively low tissue concentrations.16 The ratio of binding to the human 5-HT and NE transporters in vitro is approximately 1:10.7 In clinical studies, serotonin reuptake inhibitors block the uptake of 5-HT in platelets and decrease whole blood 5-HT concentrations.13,17 In a double-blind controlled study conducted in healthy human subjects, duloxetine reduced whole blood 5-HT versus placebo.17 In addition, increased sympathetic tone was observed with duloxetine, which is associated with significantly decreased whole body NE turnover in healthy human subjects, consistent with reuptake blockade.17 In a separate study, duloxetine in doses of 20 or 60 mg/day was found to interfere with 5-HT reuptake determined by whole blood 5-HT content in healthy human volunteers, but did not prevent an increase in blood pressure after infusion of intravenous tyramine, suggesting a lack of an effect on NE reuptake at either dose.18 However, duloxetine 60 mg was observed to increase supine systolic blood pressure in that study, indicating that this dose may reflect a threshold dose for NE reuptake inhibition.18 Higher doses may be needed to optimally block NE uptake. In healthy human subjects, 5-HT transporter occupancy in the striatum, measured using PET, was 81% after a single administration of duloxetine 40 mg/day and 82% occupancy after administration of 60 mg/day,19 the dose range recommended in the prescribing information.2 5-HT transporter occupancy increased to 84% after administration of duloxetine 60 mg/day for 7 days.19

Milnacipran has a relatively high affinity for both 5-HT and NE transporters as shown by in vitro and in vivo preclinical studies.20 Cerebral microdialysis in the hypothalamus of guinea pigs showed that extracellular levels of both 5-HT and NE were increased by milnacipran, with a ratio of 5-HT to NE uptake of roughly 2:1.20 The ratio of inhibition of cloned human 5-HT and NE transporter binding by milnacipran was approximately 1:2.9

Desvenlafaxine is the primary metabolite of venlafaxine (O-desmethylvenlafaxine [ODV]).1 Studies in animal models showed that desvenlafaxine has affinity for both 5-HT and NE transporters.21 Cells expressing either the human 5-HT transporter or NE transporter yielded Ki values for desvenlafaxine of 40.2±1.6 and 558.4±121.6 nM, respectively,8 in the same range as the parent compound. The ratio of inhibition of cloned human 5-HT and NE transporter binding by desvenlafaxine was approximately 1:14.8

None of the members of the SNRI class have shown significant binding to other transporters or receptors (eg, α1, α2, β1, or β2 adrenergic, muscarinic, histaminergic, 5-HT, or dopamine receptors, or benzodiazepine binding sites) in preclinical studies other than the 5-HT and NE transporters.7,8,16,22-24

Pharmacokinetics

The pharmacokinetic profiles of the four SNRIs are shown in Table 3.1-4,6,25-29 In contrast to many SSRIs, the SNRIs have relatively short half-lives, ranging from 5 hours (venlafaxine) to 12 hours (duloxetine).1-4 Time to peak plasma concentration ranges from 2 hours for milnacipran to 6 hours for duloxetine; steady-state plasma concentrations are achieved after 3 days for all of the SNRIs except desvenlafaxine (4 days).1-4 The pharmacokinetics for all four SNRIs are linear (dose-proportional) over their respective therapeutic ranges. Greater than 90% of duloxetine is protein-bound; venlafaxine, milnacipran, and desvenlafaxine are minimally bound to plasma proteins (Table 3).1-4,6,25-29

 

Like the SSRIs,30 metabolism of venlafaxine is primarily hepatic, via the cytochrome P450 (CYP) isozymes.1 Formation of ODV from venlafaxine is catalyzed by CYP 2D6. A clinical study has shown that patients with the CYP 2D6 poor metabolizer phenotype had higher plasma levels of venlafaxine and lower levels of ODV compared with CYP 2D6 extensive metabolizers.31 The majority of the venlafaxine dose is metabolized; ~87% appears in the urine as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), and other metabolites (27%).1 Duloxetine metabolism is primarily via CYP 2D6 and CYP 1A2.2 The majority of the duloxetine dose is metabolized; ~70% appears in the urine as metabolites and ~20% in the feces; <1% of the dose remains unchanged.2 Milnacipran is metabolized hepatically, but does not appear to involve the CYP 450 system.3,32 First pass metabolism is low33 and elimination is both renal and nonrenal; 90% of the dose is excreted renally and 50% to 60% is unchanged.3,22,32 Unlike venlafaxine, desvenlafaxine does not undergo extensive first-pass metabolism in the liver. Metabolism is primarily direct conjugation through a high-capacity (glucuronidation) pathway exclusive of the CYP 450 system, and to a lesser extent, through oxidative metabolism through N-methylation mediated by CYP 3A4.4 The pharmacokinetics of desvenlafaxine are not affected by CYP 2D6 metabolizer phenotype.4 After oral administration of desvenlafaxine, ~45% is excreted unchanged in urine, 19% excreted as a glucuronide metabolite, and <5% as the oxidative metabolite (N,O-didesmethylvenlafaxine).4

Most SSRIs are significant inhibitors of CYP 2D6, and thus have potential for interactions with concomitant drugs that are CYP 2D6 substrates.34,35 In studies that evaluated the effects of venlafaxine, desvenlafaxine, duloxetine, and paroxetine on the CYP 2D6 model substrate-drug desipramine, venlafaxine and desvenlafaxine inhibition of CYP 2D6 have been found to be weaker than both paroxetine and duloxetine,25,30,34,36,37 suggesting that both venlafaxine and desvenlafaxine have lower potential for drug-drug interactions with other CYP 2D6 substrates compared with duloxetine or paroxetine (desvenlafaxine has been found to not exert a clinically relevant effect on CYP 2D6 metabolism at the dose of 100 mg/day).4 Venlafaxine is also a weaker inhibitor of CYP 2D6 than are fluoxetine, fluvoxamine, and sertraline.34,38 Duloxetine inhibition of CYP 2D6 enzyme is lower than paroxetine but greater than sertraline.25,30

CYP 450 enzymes CYP 3A4, CYP 1A2, and CYP 2C9 are not inhibited by venlafaxine.1,34 Diazepam metabolism, which is partially metabolized by CYP 2C19, also is unaffected by venlafaxine.1 Desvenlafaxine exerts weak induction of CYP 3A4, which may lower plasma levels of drugs metabolized by this enzyme (ie, midazolam).4 In vitro, desvenlafaxine does not inhibit or induce the CYP 1A2, 2A6, 2C8, 2C9, and 2C19 isozymes.4 Duloxetine inhibits CYP 1A2; in two clinical studies, the area under the plasma concentration-versus-time curve of theophylline, a known CYP 1A2 substrate, increased by 7% and 20% when coadministered with duloxetine.2 Duloxetine does not inhibit CYP 2C9, CYP 3A, and CYP 2C19.2 Milnacipran has not been shown to interact with CYP 450 enzymes.22,29,32

Efficacy

Efficacy for the treatment of MDD has been demonstrated in randomized, placebo-controlled clinical trials for all four members of the SNRI class.39 However, the relative efficacy of the SNRIs is unclear. Currently, few head-to-head trials have been published comparing efficacy of antidepressants within the SNRI class; for this reason, the comparative efficacy of the SNRIs for treating MDD will be considered relative to other antidepressant classes. Particularly for venlafaxine, a large number of trials with active comparators have been published, with varying results. Multiple meta-analyses and pooled analyses have now been performed, generally including overlapping sets of those trials, but based on different criteria for study inclusion and measures of clinical improvement. Meta-analyses can be useful for generalizing across many trials, but when interpreting results of meta-analyses, the limitations of this type of analysis must be considered: outcomes of individual MDD trials are affected by study design (eg, open versus blinded, inclusion of active and/or placebo controls); number of patients enrolled; dose selection; treatment duration; criteria for the selection of patient population; and other factors, and these sources of variability are not controlled in the meta-analysis. For example, a meta-analysis may give equal weight to results from uncontrolled, open-label trials and randomized, double-blind, placebo-controlled trials, which provide different levels of evidence, or to studies using low versus high drug doses, short versus long treatment duration, and large versus small patient populations. Furthermore, a meta-analysis may be biased toward studies with positive results if the study sample is generated through a search of the published literature.

SNRI efficacy for treating moderate-to-severe MDD was compared with tricyclic antidepressants (TCAs) and SSRIs in a meta-analysis of head-to-head clinical trials (n=15) that included remission rates.40 The intent-to-treat (ITT) population remission rate (17-item Hamilton Rating Scale for Depression [HAM-D17]41 ≤7 or Montgomery Åsberg Depression Rating Scale [MADRS]42 ≤12) for SNRIs (49.0%) did not differ statistically from results observed for TCAs (44.1%), but was significantly higher compared with SSRIs (37.7%; P<.001). Based on a difference of >10%, the authors found the remission rates for SNRIs to be clinically superior to SSRIs. The dropout rate for SNRIs (26.1%) was significantly lower compared with TCAs (35.7%; P<.05) and did not differ statistically from SSRIs (28.4%).40

Venlafaxine

Venlafaxine was compared with TCAs and SSRIs in a meta-analysis of response rates in 44 English language, randomized, double-blind trials including ≥1 active drug43 and in a meta-analysis of effect size in 32 randomized, double-blind trials with a venlafaxine arm and ≥1 active comparator.44 Response rates based on the HAM-D17 and MADRS for ITT patients were significantly higher for venlafaxine (73.7%) than for either TCAs (57.9%) or SSRIs (61.1%; both P<.001).43 Effect size (HAM-D17, MADRS, or Clinical Global Impressions [CGI] scale45) in the second study did not show a significant difference between venlafaxine and TCAs, but favored venlafaxine over SSRIs (–0.17, 95% confidence interval [CI]: –0.27 to –0.08).44 Analysis of response and remission rates in that study favored venlafaxine over SSRIs (response: odds ratio [OR] 1.26, 95% CI: 1.02–1.58; remission: OR: 1.43, 95% CI: 1.21–1.71) but not TCAs; however, the remission analysis included only one TCA trial. In a recent meta-analysis of randomized controlled trials comparing venlafaxine with TCAs (18 trials) or SSRIs (34 trials), including both published and unpublished trials provided by the manufacturer of venlafaxine, that drug was favored over SSRIs for rates of response (OR: 1.15, 95% CI: 1.02–1.29) and remission (OR: 1.19, 95% CI: 1.06–1.34).46 Venlafaxine response and remission rates did not differ compared with TCAs (response: OR: 1.22, 95% CI: 0.96–1.54; remission: OR: 1.06, 95% CI: 0.74–1.63) using the full random effects method of analysis, but venlafaxine was favored for response rates by a conditional maximum likelihood method (OR: 1.21, 95% CI: 1.03–1.43).

Venlafaxine (immediate release [IR] and extended release [ER], study doses ranging from 37.5–399 mg/day) was compared with the SSRIs fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram in a meta-analysis of remission rates in 34 randomized, double-blind trials sponsored by the manufacturer of the drug comparing venlafaxine with an SSRI.47 Remission rates (HAM-D17 ≤7 or MADRS ≤10) favored venlafaxine over SSRIs in 28 trials while SSRIs were favored in the remaining six studies. The meta-analytic remission rate was higher for venlafaxine-treated patients compared with SSRI-treated patients (5.9% difference [95% CI: 0.038–0.081]).

Venlafaxine efficacy for MDD also was compared with SSRIs in several pooled analyses of clinical trials sponsored by the manufacturer of venlafaxine. Data pooled from eight trials comparing venlafaxine IR (75–375 mg/day) or ER (75–225 mg/day) head-to-head with the SSRIs fluoxetine (five trials; 20–80 mg/day), paroxetine (two trials; 20–40 mg/day) or fluvoxamine (one trial; 100–200 mg/day) were assessed for HAM-D17 and MADRS total score, response and remission rates, and number of MDD-free days in separate analyses.48-50 Study durations ranged from 6 to 12 weeks. In the pooled analyses (ITT population, N=2,045), there were significantly larger changes from baseline in HAM-D17 total (–14.5) and MADRS total (–17.8) scores at week 8 (using the last-observation-carried-forward [LOCF] approach) for venlafaxine compared with SSRIs (–12.6 and –15.9, respectively; both comparisons, P≤.05).48 Response rates were significantly higher for venlafaxine (HAM-D17, 64%; MADRS, 67%) than for SSRIs (HAM-D17, 57%; MADRS, 59%) at week 8.48 Final remission rates (HAM-D17 ≤7) for venlafaxine and SSRIs were 45% and 35%, respectively (P<.001), with an overall OR of 1.5 (95% CI: 1.3–1.9), indicating a 50% greater chance of remission during venlafaxine treatment than during SSRI treatment.49

Taken together, these analyses are consistent across reports and efficacy measures, and indicate that venlafaxine has superior efficacy for treating MDD compared with SSRIs. Data available suggest that it is no less effective than TCAs, as is reported for the SNRI class as a whole.40

Duloxetine

Duloxetine, venlafaxine, and fluoxetine were compared indirectly in a meta-analysis of nine duloxetine, eight venlafaxine, and 22 fluoxetine studies.51 All studies were randomized trials including a placebo arm. Study durations ranged from 8 to 9 weeks for duloxetine, 6 to 12 weeks for venlafaxine, and 5 to 12 weeks for fluoxetine. Two of the venlafaxine studies and 13 of the fluoxetine studies were small, with <60 patients in active treatment. There were no significant differences between duloxetine 40–120 mg/day and fluoxetine for meta-analytic effect size (HAM-D17) compared with placebo or for response rates. The meta-analytic effect size (0.22 [95% CI: 0.06–0.38]) and the estimated response log OR (0.70 [95% CI: 0.26–1.14]) both favored venlafaxine over duloxetine. A second indirect comparison of venlafaxine ER (three trials) and duloxetine (five trials) found no significant difference between the SNRIs for response or remission rates based on HAM-D17 or MADRS total scores.52

Duloxetine and venlafaxine were compared directly in two identically designed, randomized, double-blind trials that were analyzed together in a pooled analysis.53 Patients received venlafaxine (75–225 mg/day; n=337) or duloxetine (60–120 mg/day; n=330) for 12 weeks in flexible-dose studies. No significant differences were found between drugs for HAM-D17 total score, response rates, or remission rates after 6 or 12 weeks of treatment.53 Thus, although an indirect comparison between duloxetine and venlafaxine suggested that venlafaxine may be favored for efficacy to treat MDD, the single head-to-head comparison between the drugs does not support that finding.

Milnacipran

A meta-analysis of seven trials comparing milnacipran with TCAs indicated that milnacipran and TCAs were equally effective.54 There was no significant difference between milnacipran and TCAs for response rates based on HAM-D17 (64% and 67%, respectively) and MADRS (63% and 68%, respectively) total scores. Remission rates based on the HAM-D17 total score were 39% for milnacipran and 42% for TCAs (not statistically significant).54 The efficacy of milnacipran for MDD has been compared with SSRIs in several meta-analyses with mixed results. In the first analysis, milnacipran was compared with fluoxetine and fluvoxamine (one trial each).55 HAM-D17 response rates were 64% for milnacipran and 50% for the SSRIs (P=.01); remission rates were 39% and 28% (P=.04), respectively. In an analysis of six double-blind trials comparing milnacipran and SSRIs (fluoxetine, fluvoxamine, paroxetine), no significant differences were found in response rates.56 Papakostas and Fava56 included one trial57 that had been excluded from the earlier meta-analysis because of “an inappropriate once-daily dosage regime for milnacipran,”55 but a sensitivity analysis showed that no one trial had a significant effect on their results.56 The most recent and most comprehensive analysis included all randomized, controlled trials comparing milnacipran with any other active antidepressant monotherapy.58 A total of 16 trials were included in the analysis; seven trials included a TCA as an active comparator and eight compared milnacipran with an SSRI. No statistically significant differences were found in response or remission rates between milnacipran and TCAs or between milnacipran and SSRIs after 6–12 weeks of therapy in the meta-analysis or in any of the trials included in the analysis.58

To date, no head-to-head trials between milnacipran and any other SNRI have been published. Milnacipran is demonstrated as effective as TCAs for the treatment of MDD, but unlike venlafaxine, little data supports superiority over SSRIs.

Desvenlafaxine

Currently, there are no studies comparing desvenlafaxine with TCAs or SSRIs, but two head-to-head studies have been published comparing desvenlafaxine with venlafaxine. Desvenlafaxine 200–400 mg/day was compared with venlafaxine as an active control in two 8-week, double-blind, placebo-controlled, flexible-dose studies that were analyzed separately and pooled.59 The venlafaxine groups from the two studies were not pooled in the analysis because the dose ranges differed (75–150 mg/day and 75–225 mg/day, respectively). One of the individual studies failed: neither desvenlafaxine nor venlafaxine (75–150 mg/day) separated from placebo on the primary efficacy measure, HAM-D17 total score. In the second trial, venlafaxine-treated patients (75–225 mg/day) had significant improvement in HAM-D17 total scores compared with placebo (P=.005), but desvenlafaxine-treated patients did not. In the pooled analysis, HAM-D17 scores for desvenlafaxine and both venlafaxine groups improved significantly compared with placebo at week 8 (all P<.01). Response rates for the venlafaxine groups (64% and 57% for lower and higher-dose, respectively; both P≤.033), but not desvenlafaxine (55%), were significantly higher compared with placebo (47%). Only the higher dose venlafaxine group (36%) had significantly higher rates of remission compared with placebo (23%; P=.003; desvenlafaxine, 30%; lower dose venlafaxine, 34%).

Of the four SNRIs, venlafaxine has demonstrated the strongest efficacy for MDD, either by comparison to other antidepressant classes, or in head-to-head trials. A recent meta-analysis of 117 randomized controlled trials comparing efficacy of 12 new-generation antidepressants at therapeutic range for treating MDD found that venlafaxine had significantly better response rates compared with fluoxetine, used as a standard for comparison of all included antidepressants (OR: 1.28, 95% CI: 1.11–1.47), whereas duloxetine and milnacipran did not (desvenlafaxine was not included in the analysis).60 However, as the first SNRI, venlafaxine has been far more extensively studied, and more head-to-head trials are certainly needed to clarify whether there are real differences in efficacy within the class.

Tolerability

There are commonalities among the safety and tolerability profiles of the four SNRIs; however, there exist some important differences as well. Table 41-4 lists the most common adverse drug reactions for SNRIs. In general, SNRIs are associated with the drug reactions common to SSRIs (eg, gastrointestinal disturbances, sleep disturbance, anxiety/nervousness/agitation, sexual dysfunction)61,62 and some related to NE reuptake inhibition (eg, dry mouth, constipation, dizziness).63 Nausea is the most common adverse event (AE) for three of the four SNRIs, with incidence reported at ~20% to 40% (placebo, 7% to 12%).1,2,4 For milnacipran, nausea is not listed among the most common AEs; it is included as a less frequent AE in the prescribing information, along with other gastrointestinal disturbances.3 The more balanced 5-HT:NE selectivity ratio for milnacipran may account for the lower incidence of gastrointestinal AEs.

 

Overall, more patients treated with SNRIs discontinue due to AEs compared with placebo (venlafaxine versus placebo, 18% versus 6%, respectively, in a pooled analysis64; duloxetine, 9.7% versus 4.2%, respectively, in a pooled analysis65; desvenlafaxine 5% to 21% versus 3% to 6% in individual trials66-70; no rates of discontinuation due to AEs are reported in placebo-controlled trials of milnacipran71-73). Clinical trial evidence indicates that common adverse drug reactions with SNRIs, particularly nausea, tend to occur early in treatment and usually resolve over time.64-67 Discontinuations due to AEs increased with dose.26,65-68,70

Cardiovascular Effects and Hypertension

Earlier generation antidepressants, such as monoamine oxidase inhibitors and TCAs, are associated with adverse cardiovascular effects. Studies with SNRIs appear to show a relatively safe cardiovascular profile. Venlafaxine does not show a significant effect on heart rate,74 although venlafaxine causes an increase in blood pressure that, at higher doses, may be attributed to central inhibition of noradrenergic uptake.74 Dose-related effects of venlafaxine (75, 225, and 375 mg/day) were studied in a double-blind, placebo-controlled trial of outpatients with MDD.26 A meta-analysis of data from 2,817 venlafaxine-treated patients with MDD demonstrated a sustained increase in supine diastolic blood pressure (≥90 mm Hg) in 4.8% for venlafaxine (placebo, 2.1%; P=.037) that was highly dose-dependent: sustained elevated supine diastolic blood pressure was observed in 1.7%, 3.5%, 3.7%, and 9.1% of patients treated with ≤100 mg/day, 101–200 mg/day, 201–300 mg/day, and >300 mg/day venlafaxine, respectively.75 A cardiovascular safety profile of duloxetine was compiled using data from 1,139 duloxetine-treated and 777 placebo-treated patients in eight placebo-controlled clinical trials of MDD.76 A small mean increase in systolic blood pressure was observed with duloxetine compared with placebo (1.0 and –1.2 mm Hg, respectively), with no apparent dose effect. Sustained elevated blood pressure was observed in 1.3% of duloxetine-treated patients (placebo, 0.8%).76 Subgroup analyses of patients with an elevated blood pressure at baseline showed that neither venlafaxine nor duloxetine caused an increased risk of sustained blood pressure elevation in those patients.75,76

No comprehensive analyses of the cardiovascular safety of desvenlafaxine or milnacipran have yet been published. The prescribing information reports a small increase in systolic blood pressure for the recommended dose of desvenlafaxine (50 mg/day) compared with a decrease for the placebo group (+1.2 mm Hg, desvenlafaxine 50 mg; –1.4 mm Hg placebo). Sustained increases in blood pressure were found in some patients, particularly at the highest dose studied (400 mg/day; 2.3%).4 Rates of sustained hypertension or increased blood pressure are not reported in the prescribing information for milnacipran.3

Sexual Dysfunction

There is often confusion regarding actual rates of sexual dysfunction with antidepressant use, based on the reporting method within individual studies.77 Clinical trials often report very low incidence rates of sexual dysfunction, but those data typically represent spontaneous reports from patients and are spuriously low. Clayton and colleagues78 examined the prevalence of sexual dysfunction in a population of sexually active adult outpatients receiving antidepressant monotherapy in primary care clinics, based on total scores from the Changes in Sexual Function Questionnaire. In the overall clinical population, the prevalence of sexual dysfunction was ~40% for venlafaxine, significantly greater compared with bupropion IR (22%), and no different from any SSRI. In an analysis of data from four 8-week, double-blind, placebo- and active paroxetine-controlled MDD trials, sexual dysfunction (assessed using the Arizona Sexual Experience Scale79) was significantly less common in duloxetine-treated patients (46.4%) compared with paroxetine (61.4%; P<.015); however, both groups showed significantly greater rates of sexual dysfunction compared with the placebo group (28.8%; P=.007, P<.001, respectively).80 A separate study compared the effects of duloxetine and escitalopram versus placebo in the acute and long-term treatment of patients with MDD using the Changes in Sexual Functioning Questionnaire.81 At 8 weeks, incidence of treatment-emergent global sexual dysfunction was significantly greater than placebo (16.7%) for escitalopram (48.7%; P=.01) but not duloxetine (33.3%; P=.13). Sexual dysfunction during treatment with desvenlafaxine or milnacipran has not been assessed using a specific sexual functioning questionnaire. The prescribing information for desvenlafaxine does list male sexual function disorders as a common adverse reaction4; sexual dysfunction is not listed for milnacipran.3

Weight Change

Short-term SNRI treatment has been linked to a greater incidence of weight loss compared with placebo in patients with MDD; longer-term data show a return to baseline or small increase in weight compared with placebo.1,4,82,83 Venlafaxine ER treatment led to a loss of ≥5% of body weight in 7% of patients versus 2% in placebo-treated patients in short-term, placebo-controlled, MDD trials.1 In a long-term, placebo-controlled trial, weight loss in venlafaxine-treated patients persisted only through the third month of treatment.83 Wise and colleagues82 examined the effect of duloxetine on body weight in an analysis of 10 clinical studies of both acute (8–9 weeks) and long-term duration (26, 34, and 52 weeks). During the acute phase, duloxetine-treated patients lost more weight compared with placebo-treated patients, although the difference was small (–0.5 versus 0.2 kg respectively; P<.001). In those studies with an active comparator, similar reductions in mean weight changes compared with placebo were observed with the SSRIs fluoxetine and paroxetine. Weight change during long-term treatment (34 weeks) was not different between duloxetine 40 mg BID (0.7 kg) and placebo (0.1 kg). However, at a higher dose of duloxetine (60 mg QD), the mean weight change (0.9 kg) was similar to paroxetine 20 mg QD (1.0 kg) and significantly greater compared with placebo (0.1 kg, both P<.05). Mean weight gain for milnacipran (50, 100, or 200 mg/day) was significantly less compared with an active comparator in two separate studies (amitriptyline,84 fluoxetine85), but no comparison of weight gain for milnacipran versus placebo was reported. Desvenlafaxine at doses of 50, 100, 200, and 400 mg/day was associated with weight loss of –0.4, –0.6, –0.9, and –1.1 kg, respectively, compared with no change in the placebo group in short-term, fixed-dose, controlled studies.4 In a study of patients who responded to desvenlafaxine during an initial 12-week, open-label phase, a subsequent 6-month, double-blind, placebo-controlled phase showed no statistical difference in mean weight change between desvenlafaxine and placebo at the final on-therapy assessment.4

Discontinuation Symptoms

Discontinuation symptoms have been reported after abrupt discontinuation of each of the SNRIs. Emergence of discontinuation symptoms was studied in a population of 20 outpatients with MDD who had participated in a double-blind, placebo-controlled study of the efficacy and safety of venlafaxine (75 mg/day).86 Seven of nine (78%) venlafaxine-treated subjects showed discontinuation symptoms compared with only two of nine (22%) in the placebo group during the 3 days following drug discontinuation (P<.03). The most common discontinuation symptoms after venlafaxine withdrawal were dizziness, excessive sweating, irritability, dysphoria, and insomnia. Discontinuation symptoms following abrupt withdrawal of duloxetine (20–60 mg BID or 60 mg QD) were examined in a pooled analysis of six short-term treatment trials of 8–9 weeks duration.87 A greater proportion of the SNRI-treated patients (44.3%) exhibited discontinuation symptoms compared with the placebo group (22.9%; P<.05). Discontinuation symptoms that occurred significantly more frequently after abrupt withdrawal of duloxetine compared with placebo were dizziness (12.4%), nausea (5.9%), headache (5.3%), paraesthesia (2.9%), vomiting (2.4%), irritability (2.4%), and nightmares (2%). Discontinuation symptoms associated with long-term treatment of duloxetine ≤52 weeks also were studied; no increase in incidence or severity of symptoms was reported.87 Discontinuation symptoms were examined following discontinuation of treatment with milnacipran (100 mg/day) compared with paroxetine (20 mg/day) in patients with MDD.88 After a 6-week treatment, abrupt withdrawal led to discontinuation symptoms in 13% of the milnacipran group compared with 31.8% of the paroxetine group. In those patients who completed an additional 18-week extension, discontinuation symptoms were observed in 30% of the milnacipran group compared with 30.3% of the paroxetine group. The most frequently reported AE following treatment withdrawal after 24 weeks of treatment in the milnacipran group was anxiety as compared with dizziness, anxiety, and nausea in the paroxetine group. Discontinuation symptoms have been observed in patients with MDD who undergo abrupt discontinuation or dose reduction of desvenlafaxine.4 These symptoms include dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety, fatigue, abnormal dreams, and hyperhidrosis.

Dosing

The recommended initial starting dose of venlafaxine ER is 75 mg/day with some patients, although a 37.5 mg capsule is available if needed. In those patients who do not respond to the 75 mg/day dose, increases to a maximum of ~225 mg/day of venlafaxine ER is recommended at increments of 75 mg/day at intervals not less than 4 days.1 However, venlafaxine IR was approved in doses ≤375 mg/day, suggesting that this drug has a very wide therapeutic dosing range. Rudolph and colleagues26 reported that for patients treated with venlafaxine 75, 225, or 375 mg/day, higher doses resulted in greater improvement in MDD scores (HAM-D21, MADRS, and CGI-S). In a separate study that included venlafaxine 75, 150, and 200 mg/day dose groups, Khan and colleagues89 found that statistical separation from placebo for patient response rates (based on HAM-D and CGI scales) was achieved earlier in treatment with increasing dose, with significantly higher rates compared with placebo starting at weeks 4, 3, and 2, for the three venlafaxine dose groups, respectively.

The dose-response relationship of duloxetine at fixed doses of 40, 60, 80, and 120 mg/day was characterized in an analysis of data from six double-blind, randomized, placebo-controlled clinical trials assessing efficacy using HAM-D6 scores in patients with MDD.90 Duloxetine 40 mg/day yielded an effect size of 0.40, whereas duloxetine 80 and 120 mg/day reached an effect size >.40. A numerically greater effect size was found in response to duloxetine 120 mg/day as compared with duloxetine 60 and 80 mg/day, but the difference was not statistically significant. Based on these studies, duloxetine 60 mg/day was determined to be the optimal effective dose for the treatment of patients with MDD.90

There is some suggestion of a dose effect for milnacipran, but few doses have been tested.27,28,56,91,92 In a population of patients with MDD or bipolar disorder, milnacipran 100 mg/day was found to have a faster onset of action than milnacipran 50 mg/day with a cumulative improved percentage of responder patients (as defined as a 50% reduction from baseline total scores on the HAM-D) with >80% response at 4 and 6 weeks, respectively.28 Milnacipran 150 mg/day was also found to provide significant improvement over 75 mg/day in both response and remission as assessed by the HAM-D in patients with MDD.27 In another study of patients with MDD, milnacipran was shown to be effective when administered at a 50 mg/day dose during the first week, and 100 mg/day afterward, with no relationship between MDD scores and plasma milnacipran levels.91 The recommended dose of milnacipran is 100 mg/day in two divided 50 mg/day doses.3

Clinical studies have demonstrated efficacy of desvenlafaxine at doses of 50–400 mg/day.66-68 No additional benefits were observed at doses >50 mg/day, but AEs and discontinuations were more frequent at higher doses.66-68 Thus, the recommended dose of desvenlafaxine is 50 mg/day.4

Unmet Needs Regarding Antidepressant Therapy

Management of Comorbid Conditions

Although MDD and anxiety are distinct illnesses, both may occur in the same patient and share some underlying pathophysiology.93 Virtually all antidepressant classes and newer atypical antidepressants have shown efficacy for treating anxiety disorders.93,94 SSRIs exert significant effects in the treatment of anxiety disorders, including panic disorder, obsessive-compulsive disorder, and social phobia. Dual reuptake inhibitors are also effective in anxiety disorders.93 Dunner and colleagues95 concluded that the SNRI duloxetine was effective in the treatment of comorbid anxiety symptoms associated with MDD. In pooled data from four studies in which duloxetine 60 mg/day yielded superiority over placebo on the HAM-D17 total depression score, duloxetine demonstrated efficacy over placebo in treating anxiety symptoms as well, as measured by the HAM-D anxiety/somatization subfactor and anxiety-psychic item.95 Venlafaxine ER also has been shown to be efficacious in the treatment of patients with MDD with comorbid anxiety.96 For example, in a prospective, 12-week, randomized, double-blind, placebo-controlled trial of MDD patients with anxiety, venlafaxine ER was shown to be superior to fluoxetine on the Hamilton Rating Scale for Anxiety (HAM-A)97 (65% versus 51%, respectively, [placebo 39%]; P<.05).96

Although no clinical trial data are available assessing effects of desvenlafaxine on anxiety symptoms as a primary end point, data from placebo-controlled MDD trials suggest that this SNRI can also reduce anxiety symptoms in MDD patients. Scores on the Covi Anxiety Scale were significantly reduced compared with placebo in an 8-week trial of desvenlafaxine (50 and 100 mg/day)70 and in a pooled analysis of two flexible-dose trials (200 and 400 mg/day)59; however, a second fixed-dose trial showed no effect of desvenlafaxine (50 and 100 mg/day) on Covi scores.66 The efficacy of milnacipran for treating anxiety or anxiety symptoms in MDD has not been assessed in placebo-controlled trials.

Treatment-resistant Depression

Over half of all MDD patients may fail to remit with antidepressant treatment: in a meta-analysis of 2,458 patients treated with TCAs, SSRIs, or SNRIs in 15 studies, remission rates ranged from 37.7% for SSRIs to 49% with SNRIs.40 When MDD patients fail to adequately respond to a first-line antidepressant, three strategies for subsequent pharmacotherapy are available: switch to a different drug in the same class, switch to a different class of antidepressants, or augment with another drug.98 Results from several randomized controlled trials suggest that switching to venlafaxine may be more effective after SSRI failure than switching to another SSRI. Patients with treatment-resistant depression (ie, having a history of resistance to two successive antidepressant treatments for the current episode) treated for 4 weeks with venlafaxine (200–300 mg/day) had HAM-D response and remission rates of 52% and 42%, respectively, compared with 33% and 20%, respectively, for patients treated with paroxetine (30–40 mg/day; both P<.05).99 In a single-blind study of elderly patients with MDD who had previously failed two rounds of antidepressant therapy (an SSRI followed by a TCA or heterocyclic antidepressant), venlafaxine (mean dose=165 mg/day) was found to be superior to paroxetine (mean dose=26 mg/day) on CGI and HAM-D measures (both P<.05).100 However, other randomized controlled trials have found no advantage to switching to venlafaxine over a second SSRI; in the second treatment step of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial,101 patients who did not remit (>5 on the 16-item Quick Inventory of Depressive Symptomatology–Clinician-Rated102) after 12 weeks of treatment with citalopram (mean exit dose=42 mg/day) were randomly assigned to receive sertraline (≤200 mg/day), venlafaxine (≤375 mg/day), or bupropion (≤400 mg/day) for ≤14 weeks in an open-label trial.103 Approximately 25% of patients achieved remission; response and remission rates did not differ among treatment groups. In the Treatment of SSRI-Resistant Depression in Adolescents trial, 100 patients aged 12–18 years with a CGI-S score of ≥4 after at least 8 weeks of treatment with an SSRI were randomly assigned to receive venlafaxine or a second SSRI, with or without cognitive-behavioral therapy (CBT). Response rates were higher in patients who were treated with CBT compared to those who did not receive CBT, but there was no significant difference between the venlafaxine and SSRI groups.104 Currently, duloxetine has only been assessed in switch studies with no active or placebo comparators,105 and no studies assessing the efficacy of milnacipran or desvenlafaxine after switch have been published. Despite some encouraging data for venlafaxine, treatment-resistant depression is still a major unmet need as the response rates of patients on antidepressant therapy—whether SSRI, SNRI, or an alternative—remain insufficient.106

Conclusion

All four SNRIs have demonstrated efficacy similar to TCAs for the treatment of MDD. The extensive efficacy data available for venlafaxine suggests that it may be superior to SSRIs, whereas there is no evidence yet to indicate that duloxetine, milnacipran, or desvenlafaxine also show superior efficacy. The available data suggest that the safety and tolerability of the SNRIs are comparable, with two notable exceptions: sustained hypertension is observed in almost 10% of patients treated with high doses of venlafaxine, but at much lower levels for duloxetine and desvenlafaxine; and milnacipran may be associated with fewer AEs, and in particular, lower levels of nausea. However, because few placebo-controlled studies of milnacipran for MDD have been published, and because conventions for reporting AE data outside of the US differ from those used in US prescribing information, it is difficult to draw conclusions from the currently available data. Additional head-to-head trials are necessary to confirm these possible differences in efficacy and safety within the SNRI class. PP

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